Regulation of Intronic Polyadenylation by PCF11 Impacts mRNA Expression of Long Genes

Cell Rep. 2019 Mar 5;26(10):2766-2778.e6. doi: 10.1016/j.celrep.2019.02.049.

Abstract

Regulation of cleavage and polyadenylation (CPA) affects gene expression and polyadenylation site (PAS) choice. Here, we report that the CPA and termination factor PCF11 modulates gene expression on the basis of gene size. Although downregulation of PCF11 leads to inhibition of short gene expression, long genes are upregulated because of suppressed intronic polyadenylation (IPA) enriched in large introns. We show that this regulatory scheme, named PCF11-mediated expression regulation through IPA (PEIPA), takes place in cell differentiation, during which downregulation of PCF11 is coupled with upregulation of long genes with functions in cell morphology, adhesion, and migration. PEIPA targets distinct gene sets in different cell contexts with similar rules. Furthermore, PCF11 is autoregulated through a conserved IPA site, the removal of which leads to global activation of PASs close to gene promotors. Therefore, PCF11 uses distinct mechanisms to regulate genes of different sizes, and its autoregulation maintains homeostasis of PAS usage in the cell.

Keywords: 3ʹ; alternative polyadenylation; autoregulation; cell differentiation; end processing; gene size; intron size; intronic polyadenylation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions
  • 3T3-L1 Cells
  • Animals
  • Cell Differentiation / genetics
  • Cell Proliferation / genetics
  • Gene Expression Regulation*
  • Gene Knockout Techniques
  • Humans
  • Introns*
  • Mice
  • NIH 3T3 Cells
  • Polyadenylation
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • mRNA Cleavage and Polyadenylation Factors / genetics*
  • mRNA Cleavage and Polyadenylation Factors / metabolism*

Substances

  • 3' Untranslated Regions
  • Pcf11 protein, human
  • RNA, Messenger
  • mRNA Cleavage and Polyadenylation Factors